Molecular heterogeneity in systemic sclerosis skin: insights from single-cell and spatial omics, and implications for disease stratification and cutaneous assessment.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by skin and internal organ fibrosis, vasculopathy and immune dysregulation. Skin fibrosis, commonly assessed using the modified Rodnan skin score (mRSS), remains a defining feature of SSc and is associated with disease severity and prognosis. However, conventional clinical assessment provides limited insight into the molecular heterogeneity underlying cutaneous involvement. Single-cell RNA sequencing and spatial transcriptomics have shown that SSc skin contains distinct fibroblast states, immune-stromal interactions and spatially organized fibrotic niches. These data challenge the view of cutaneous fibrosis as a uniform process and instead support a model in which different cellular and spatial programmes may contribute to clinically similar patterns of skin involvement. In this review, we synthesize the findings from single-cell and spatial multi-omics studies of SSc skin published between 2021 and 2025, examine the extent to which molecular heterogeneity relates to clinical phenotype, and discuss the implications for cutaneous assessment, treatment response heterogeneity and biologically informed patient subgrouping. Because skin biopsy is clinically accessible and can be repeated over time, it provides a practical setting in which these molecular observations can be studied. Whether they improve patient stratification, treatment selection or cutaneous outcome assessment will depend on prospective validation in larger and clinically well-characterized cohorts.